Multiple Escalating Oral Doses Study of PF-07081532 in Adult Participants With Type 2 Diabetes Mellitus

The pre-specified categorical analysis criteria in ECG, were PR interval: value ≥ 300 milliseconds (msec), percentage change ≥ 25/50%; QRS duration: value ≥140 msec, percentage change ≥ 50%; QTcF interval: 450 \< value ≤ 480 msec, 480 \< value ≤ 500 msec, value \>500 msec, and 30\<change ≤ 60 msec, change \>60 msec.

Time frame: From Baseline to 7-14 days following last dose administration (that is a maximum of 42 days from baseline for Part A and a maximum of 56 days from baseline for Part B and Part C)

Population: The population for this outcome measure included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.

Participants with laboratory abnormalities with ≥2 occurrences (without regard to baseline abnormality) that met pre-specified criteria were High-density lipoprotein (HDL) Cholesterol \<0.8✕ lower limit of normal (LLN); Bicarbonate \<0.9✕LLN; Calcitonin\>1.0✕upper limit of normal (ULN); Triglycerides \>1.3✕ULN; Aspartate Aminotransferase \>3.0✕ULN; Low-density lipoprotein (LDL) Cholesterol \>1.2✕ULN; Urine Glucose ≥1; Urine Ketones ≥1; Urine Leukocyte Esterase ≥1; Urine Leukocytes ≥20; Urine Hyaline Casts \>1; Urine Hemoglobin ≥1; and Urine Nitrite ≥1.

Time frame: From Baseline to 7-14 days following last dose administration (that is a maximum of 42 days from baseline for Part A and a maximum of 56 days from baseline for Part B and Part C)

Population: The population for this outcome measure included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An serious adverse event (SAE) was defined as an AE: 1. resulting in death, 2. was life-threatening, 3. required inpatient hospitalization or prolongation of existing hospitalization, 4. resulted in persistent disability, 5. was a congenital anomaly/birth defect, or considered to be an important medical event. Treatment-related AE was any untoward medical occurrence attributed to study intervention in a participant who received study intervention. Treatment-emergent are events between first dose of study intervention and up to 28-35 days after last dose that were absent before treatment or that worsened relative to pretreatment state.

Time frame: From the first dose up to 28-35 days after last administration of study intervention (that is a maximum of 63 days from first dose for Part A and a maximum of 77 days from first dose for Part B and Part C)

Population: The population for this outcome measure included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.

Vital signs (pulse rate, systolic and diastolic blood pressure) were obtained with participant in the supine position. The pre-specified categorical analysis criteria in vital signs, were supine systolic blood pressure \< 90 millimeters of mercury (mmHg), supine systolic blood pressure increase/decrease from baseline ≥ 30mmHg; supine diastolic blood pressure \<50 mmHg, supine diastolic blood pressure increase/decrease from baseline ≥ 20mmHg; pulse rate \<40 beats per minute (bpm) or \>120 bpm.

Time frame: From Baseline to 7-14 days following last dose administration (that is a maximum of 42 days from baseline for Part A and a maximum of 56 days from baseline for Part B and Part C)

Population: The population for this outcome measure included all participants randomly assigned to study intervention and who took at least 1 dose of study intervention. Participants were analyzed according to the study intervention they actually received.

AUC24 is defined as area under the concentration-time profile from time 0 to 24 hours using Linear/Log trapezoidal method.

Time frame: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Days 1 and 28 for Part A, on Days 1 and 42 for Part B and Part C

Population: The population for this outcome measure included all randomized participants who received at least 1 dose of PF-07081532 and had at least 1 of the pharmacokinetics (PK) parameters of interest calculated.

Ae24 is defined as cumulative amount of drug recovered unchanged in urine over 24 hours using the method of urine concentration \* volume of urine.

Time frame: Part A: Day 28 (0-24 hours). Part C : Day 42 (0-24 hours)

Population: The population for this outcome measure included all randomized participants with T2DM who received at least 1 dose of PF-07081532 and had at least 1 of the PK parameters of interest calculated.

Cmax is defined as maximum plasma concentration observed directly from data.

Time frame: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Days 1 and 28 for Part A, on Days 1 and 42 for Part B and Part C

Population: The population for this outcome measure included all randomized participants who received at least 1 dose of PF-07081532 and had at least 1 of the PK parameters of interest calculated.

Ae24% is defined as percent of dose recovered unchanged in urine over the 24 hours using the method of 100 \* Ae24/Dose

Time frame: Part A: Day 28 (0-24 hours). Part C : Day 42 (0-24 hours)

Population: The population for this outcome measure included all randomized participants with T2DM who received at least 1 dose of PF-07081532 and had at least 1 of the PK parameters of interest calculated.

Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine over the dosing interval tau (Aetau) divided by area under the concentration time-curve from time 0 to time tau (AUCtau)

Time frame: Part A: Day 28 (0-24 hours). Part C : Day 42 (0-24 hours)

Population: The population for this outcome measure included all randomized participants with T2DM who received at least 1 dose of PF-07081532 and had at least 1 of the PK parameters of interest calculated.

t1/2 is defined as the time measured for the plasma concentration to decrease by one half.

Time frame: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Day 28 for Part A, on Day 42 for Part B and Part C

Population: The population for this outcome measure included all randomized participants who received at least 1 dose of PF-07081532 and had at least 1 of the PK parameters of interest calculated.

Tmax is defined as time for Cmax observed directly from data as time of first occurrence.

Time frame: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24 hours post-dose on Days 1 and 28 for Part A, on Days 1 and 42 for Part B and Part C

Population: The population for this outcome measure included all randomized participants who received at least 1 dose of PF-07081532 and had at least 1 of the PK parameters of interest calculated.